Bioabsorbable drug delivery devices

ABSTRACT

A bioabsorbable drug delivery device and various methods of making the same. The devices are preferably formed from bioabsorbable materials using low temperature fabrication processes, whereby drugs or other bio-active agents are incorporated into or onto the device and degradation of the drugs or other agents during processing is minimized. Radiopaque markers may also be incorporated into, or onto, the devices. The devices may be generally tubular helical stents comprised of a solid ladder or an open lattice configuration, or a hybrid combination thereof. The tubular helical stents are generally formed from precursor fibers, films or tubes. The solid ladder configuration provides increased radiopacity and increased radial strength, whereas the open lattice configuration provides better endothelialization and fluid flow through the stent. The drug or other agent delivery capacity of the devices may provide local or regionalized drug or other agent delivery, or a combination thereof, with more consistent concentrations of drugs or other agents delivered from the device to the treatment site along the entire length of the device.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention generally relates to bioabsorbable drug delivery devicesand methods of making the same. More specifically, the invention relatesto drug delivery devices comprised of bioabsorbable materials formedinto desired geometries by different polymer processing methods.

2. Related Art

Intraluminal endovascular stents are well-known. Such stents are oftenused for repairing blood vessels narrowed or occluded by disease, forexample, or for use within other body passageways or ducts. Typicallythe stent is percutaneously routed to a treatment site and expanded tomaintain or restore the patency of the blood vessel or other passagewayor duct within which the stent is placed. The stent may be aself-expanding stent comprised of materials that expand after insertionaccording to the body temperature of the patient, or the stent may beexpandable by an outwardly directed radial force from a balloon, forexample, whereby the force from the balloon is exerted on an innersurface of the stent to expand the stent towards an inner surface of thevessel or other passageway or duct within which the stent is placed.Ideally, once placed within the vessel, passageway or duct, the stentwill conform to the contours and functions of the blood vessel,passageway or duct in which the stent is deployed.

Moreover, as in U.S. Pat. No. 5,464,450, stents are known to becomprised of biodegradable materials, whereby the main body of the stentdegrades in a predictably controlled manner. Stents of this type mayfurther comprise drugs or other biologically active agents that arecontained within the biodegradable materials. Thus, the drugs or otheragents are released as the biodegradable materials of the stent degrade.

Although such drug containing biodegradable stents, as described in U.S.Pat. No. 5,464,450, may be formed by mixing or solubilizing the drugswith the biodegradable polymer comprising the stent, by dispersing thedrug into the polymer during extrusion of the polymer, or by coating thedrug onto an already formed film or fiber, such stents typically includerelatively small amounts of drugs. For example, U.S. Pat. No. 5,464,450contemplates containing only up to 5% aspirin or heparin in its stentfor delivery therefrom. Moreover, the profile of drugs delivered fromsuch stents tend to concentrate the drugs at a primary region of thestent rather than delivering drugs more uniformly along a length of thestent. Lengthwise delivery of drugs from a stent could enhance treatmentof a targeted site, disease or condition. Further, such stents asdisclosed in U.S. Pat. No. 5,464,450 are often made without radiopaquemarkers. The omission of radiopaque markers inhibit the visualizationand accurate placement of the stent by the medical practitioner. Furtherstill, stents produced by melt-spinning a polymer into fibers containingdrugs in accordance with U.S. Pat. No. 5,464,450 tend to stretch thefibers as monofilaments at temperatures of 50°-200° C. This processsuggests the drugs incorporated into the stents are stable at hightemperatures. Because relatively few high temperature stable drugsexist, this limits polymer processing options significantly for stentsor other drug delivery devices.

Polymers are often processed in melt conditions and at temperatures thatmay be higher than is conducive to the stability of the drugs or otheragents to be incorporated into a bioabsorbable drug delivery device.Typical methods of preparing biodegradable polymeric drug deliverydevices, such as stents, include fiber spinning, film or tube extrusionor injection molding. All of these methods tend to use processingtemperatures that are higher than the melting temperature of thepolymers. Moreover, most bioabsorbable polymers melt process attemperatures at which most drugs are not stable and tend to degrade.

Stents of different geometries are also known. For example, stents suchas disclosed in U.S. Pat. No. 6,423,091 are known to comprise a helicalpattern comprised of a tubular member having a plurality of longitudinalstruts with opposed ends. Such helical patterned stents typically haveadjacent struts connected to one another via the ends. The pitch, orangle, of the longitudinal struts as it wraps around the tubular stentin the helical configuration is typically limited, however, by themanner in which the longitudinal struts are made. Limiting the pitch orangle of the longitudinal struts of such helical stents can adverselyaffect the radial strength of such stents.

In view of the above, a need exists for systems and methods that formimplantable bioabsorbable polymeric drug delivery devices with desiredgeometries or patterns, wherein the devices have increased and moreeffective drug delivery capacity and radiopacity. Further in view of theabove, a need exists for systems and methods wherein degradation of thedrugs incorporated into the devices during processing is minimized.Still further in view of the above, a need exists for systems andmethods that form the bioabsorbable devices into geometries havingimproved radial strength and variable strut pitch capabilities andconfigurations, and having increased and more effective drug deliverycapacity and radiopacity.

SUMMARY OF THE INVENTION

The systems and methods of the invention provide bioabsorbable polymericdrug delivery devices with increased and more effective drug deliverycapacity and increased radiopacity.

According to the systems and methods of the invention, the devices arepreferably formed from bioabsorbable polymers using low temperaturefabrication processes. Preferred low temperature processes for preparingdifferent structures such as films, fibers and tubes include solutionprocessing and extrusion, melt processing using solvents andplasticizers, processing from gels and viscous solutions, andsuper-critical fluid processing, whereby drugs that are not stable athigh temperatures are able to be incorporated into the polymer formingthe device. Different processing methods can further include solventextraction, coating, co-extrusion, wire-coating, lyophilization,spinning disk, wet and dry fiber spinning, electrostatic fiber spinning,and other processing methods known in the art. The preferred lowtemperature processes increases the number or concentration of drugs orother agents that may be incorporated into the drug delivery devicesmade according to the systems and methods of the invention. For drugswith high temperature stability, a variety of high temperature meltprocessing methods, including extrusion, co-extrusion, fiber spinning,injection molding, and compression molding may also be used to form thedevices according to the invention. Different geometries and performancecharacteristics of the drug delivery devices are achieved according tothe different processes and materials used to make the devices.

In some embodiments, the drug delivery device is a stent comprised ofbioabsorbable polymers with drugs or other bio-active agents andradiopaque markers incorporated therein. The drugs or other bio-activeagents are incorporated into, or coated onto, the stent in significantlygreater amounts than in prior art stents. Likewise, radiopaque markersmay be provided in or on the stent. The combination of greater amountsof drugs, or other agents, for delivery from the device with theradiopaque markers tends to improve the treatment of a targeted site,disease or condition and the visualization and placement of the devicein the patient.

In a preferred embodiment, the drug delivery device is a stent comprisedeither of a tubular or a helical configuration wherein the radiopacity,radial strength, flexibility and other performance attributes of thedevice are optimized by different design parameters. In the case of ahelical configuration, radial strength of the stent tends to beincreased by a generally solid ladder configuration. Alternatively,endothelialization of the device and flow therethrough is increased by agenerally open lattice structure with high surface area. Hybrid designscombining the solid ladder with the open lattice structure providesaspects of increased radial strength and improved endothelialization andflow therethrough. The helical design also provides flexibility andbending properties to treat disease states in various anatomical regionssuch as the superior femoral artery or below the knee.

Other embodiments of the systems and methods of the invention compriseforming a non-stent device such as a ring, or wrap, drug deliverydevice. The ring, or wrap, is similarly comprised of bioabsorbablematerials wherein drugs or other agents and radiopaque markers areincorporated therein. The bioabsorbable materials are similarlyprocessed according to the various processes outlined above with respectto the formation of the stents but are shaped in the appropriate ring,or wrap, geometry or pattern as desired.

The bioabsorbable polymeric materials that comprise the stent or otherdevice according to the systems and methods of the invention are chosenbased on several factors, including degradation time, retention of themechanical properties of the stent or other device during the activedrug delivery phase of the device, and the ability of the bioabsorbablematerials to be processed into different structures and via differentmethods. Other factors, including processing and material costs andavailability, may also be considered.

The types of bioabsorbable polymers contemplated by the systems andmethods of the invention include, but are not limited to, bulk orsurface erosion polymers that are hydrophilic or hydrophobic,respectively, and combinations thereof. These polymers tend to helpcontrol the drug delivery aspects of the stent or other drug deliverydevice. Other bioabsorbable polymeric materials that may comprise thestent or other drug delivery device according to the systems and methodsof the invention are shape memory polymers, polymer blends, and/orcomposites thereof that contribute to retaining the mechanical integrityof the device until drug delivery is completed.

Because polymers are generally not radiopaque, the bioabsorbablepolymeric materials comprising the drug delivery device according to thesystems and methods of the invention may include additives to enhancethe radioapacity of the stent or other drug delivery device. Suchradiopaque additives may include inorganic fillers, metal powders, metalalloys or other materials known or later developed in the art.Alternatively, the device may be coated with radiopaque material. Theradiopaque additives or coatings may be applied uniformly throughout orover the stent or device, or may be applied only to designated sectionsof the stent or device as markers.

The above and other features of the invention, including various noveldetails of construction and combinations of parts, will now be moreparticularly described with reference to the accompanying drawings andclaims. It will be understood that the various exemplary embodiments ofthe invention described herein are shown by way of illustration only andnot as a limitation thereof. The principles and features of thisinvention may be employed in various alternative embodiments withoutdeparting from the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects, and advantages of the apparatus andmethods of the present invention will become better understood withregard to the following description, appended claims, and accompanyingdrawings where:

FIG. 1 illustrate a helical solid ladder stent in a deployed state, aballoon mounted state and in a film cut precursor state according to thesystems and methods of the invention.

FIG. 2 illustrates a helical open lattice stent according to the systemsand methods of the invention.

FIG. 3 illustrates a helical stent having a hybrid solid ladder and openlattice design in a deployed state, a balloon mounted state, and in afilm cut precursor state according to the systems and methods of theinvention.

FIGS. 4 a-4 c illustrate various embodiments of a ring, or wrap,according to the systems and methods of the invention.

FIG. 5 a illustrates a cut film strip having an exemplary dimensionalscheme for a solid ladder stent according to the systems and methods ofthe invention.

FIG. 5 b illustrates a solid ladder stent in a deployed state withsquared ends.

FIG. 6 a illustrates a cut film strip having an exemplary dimensionalscheme for an open lattice stent according to the systems and methods ofthe invention.

FIG. 6 b illustrates an open lattice stent in a deployed state withsquared ends.

FIG. 7 illustrates a flow diagram of a film fabrication processaccording to the systems and methods of the invention.

FIG. 8 illustrates a flow diagram of a tube fabrication processaccording to the systems and methods of the invention.

FIG. 9 illustrates a graph showing drug uptake in vessel tissueaccording to the systems and methods of the invention.

FIG. 10 illustrates a graph showing drug elution pharmacokineticsaccording to the systems and methods of the invention.

DETAILED DESCRIPTION OF THE INVENTION

According to the systems and methods of the invention, a drug deliverydevice comprised of bioabsorbable materials is made by any of a varietyof processes. The drug delivery devices can be prepared bysolution-based processes using solvents as by, for example, fiberspinning (dry and wet spinning), electrostatic fiber spinning, spinningdisk (thin films with uniform thickness), lyophilization, extrusion andco-extrusion, co-mingled fibers, supercritical fluids, solvent castfilms, or solvent cast tubes, wherein low temperature processing ispreferred. Alternatively, the drug delivery devices can be prepared bymore conventional polymer processing methods in melt condition as by,for example, extrusion, co-extrusion, injection molding and compressionmolding. The artisan should readily appreciate the general techniquesattendant with the various methods referred to above and, except asotherwise provided herein, detailed explanations thereof are omitted forbrevity but understood to be included herein.

The processes used to prepare the drug delivery devices are preferablylow temperature processes in order to minimize degradation of drugs orother bio-active agents that are incorporated into the matrix ofbioabsorbable polymeric materials comprising the device. To this end,processing methods may comprise forming the device from bioabsorbablepolymeric materials via low temperature, solution-based processes usingsolvents as outlined above and discussed in greater detail furtherbelow.

The drug delivery devices according to the systems and methods of theinvention can be disease specific, and can be designed for local orregional therapy, or a combination thereof. The drugs or other agentsdelivered by the drug delivery devices according to the systems andmethods of the invention may be one or more drugs, bio-active agentssuch as growth factors or other agents, or combinations thereof. Thedrugs or other agents of the device are ideally controllably releasedfrom the device, wherein the rate of release depends on either or bothof the degradation rate of the bioabsorbable polymers comprising thedevice and the nature of the drugs or other agents. The rate of releasecan thus vary from minutes to years as desired. Surface erosion polymersor bulk erosion polymers, for example, can be used as the bioabsorbablepolymer in order to better control the drug delivery therefrom.

Surface erosion polymers are typically hydrophobic with water labilelinkages. Hydrolysis tends to occur fast on the surface of such surfaceerosion polymers with no water penetration in bulk. The drug releaserate from devices comprised of such surface erosion polymers can thus bevaried linearly while maintaining the mechanical integrity of thedevice. The initial strength of such surface erosion polymers tends tobe low however, and often such surface erosion polymers are not readilyavailable commercially. Nevertheless, examples of surface erosionpolymers that could be used to help vary the drug delivery rate of adevice according to the systems and methods of the invention includepolyanhydrides such as poly(carboxyphenoxy hexane-sebacic acid),poly(fumaric acid-sebacic acid), poly(carboxyphenoxy hexane-sebacicacid), poly(imide-sebacic acid)(50-50), poly(imide-carboxyphenoxyhexane)(33-67), and polyorthoesters (diketene acetal based polymers).

Bulk erosion polymers, on the other hand, are typically hydrophilic withwater labile linkages. Hydrolysis of bulk erosion polymers tends tooccur at more uniform rates across the polymer matrix of the device. Asa result, bulk erosion polymers release initial bursts of drugs duringbreakdown of the polymer matrix during absorption. Bulk erosion polymersexhibit superior initial strength and are readily availablecommercially.

Examples of bulk erosion polymers usable with the drug delivery devicesaccording to the system and methods of the invention includepoly(α-hydroxy esters) such as poly (lactic acid), poly(glycolic acid),poly(caprolactone), poly(p-dioxanone), poly (trimethylene carbonate),poly(oxaesters), poly(oxaamides), and their co-polymers and blends. Somecommercially readily available bulk erosion polymers and their commonlyassociated medical applications include poly(dioxanone) [PDS® sutureavailable from Ethicon, Inc., Somerville, N.J.], poly(glycolide) [Dexon®sutures available from United States Surgical Corporation, North Haven,Conn.], poly(lactide)-PLLA [bone repair], poly(lactide/glycolide)[Vicryl® (10/90) and Panacryl® (95/5) sutures available from Ethicon,Inc., Somerville, N.J.], poly(glycolide/caprolactone (75/25) [Monocryl®sutures available from Ethicon, Inc., Somerville, N.J.], and poly(glycolide/trimethylene carbonate) [Maxon® sutures available from UnitedStates Surgical Corporation, North Haven, Conn.].

Other bulk erosion polymers are also usable with the drug deliverydevices according to the systems and methods of the invention, forexample, tyrosine derived poly amino acid [examples: poly(DTHcarbonates), poly(arylates), and poly(imino-carbonates)], phosphorouscontaining polymers [examples: poly(phosphoesters) and poly(phosphazenes)], poly(ethylene glycol) [PEG] based block co-polymers[PEG-PLA, PEG-poly(propylene glycol), PEG-poly(butylene terphthalate)],poly(α-malic acid), poly(ester amide), and polyalkanoates [examples:poly(hydroxybutyrate (HB) and poly (hydroxyvalerate) (HV) co-polymers].

Of course, according to the systems and methods of the invention, thedrug delivery devices may be made from combinations of surface and bulkerosion polymers in order to achieve desired physical properties and tocontrol the degradation mechanism and drug release therefrom as afunction of time. For example, two or more polymers may be blended inorder to achieve desired physical properties, device degradation rateand drug release rate. Alternatively, the drug delivery device can bemade from a bulk erosion polymer that is coated with a drug containing asurface erosion polymer. For example, the drug coating can besufficiently thick that high drug loads can be achieved, and the bulkerosion polymer may be made sufficiently thick that the mechanicalproperties of the device are maintained even after all of the drug hasbeen delivered and the surface eroded.

While the degradation and drug release factors are considered inchoosing the bioabsorable polymers that are to comprise the drugdelivery device according to the systems and methods of the invention,maintaining the mechanical integrity and resilience of the device isalso a factor to consider. In this regard, shape memory polymers help adevice to maintain, or remember, its original shape after deployment ofthe device in the patient. Shape memory polymers are characterized asphase segregated linear block co-polymers having a hard segment and asoft segment. The hard segment is typically crystalline with a definedmelting point, and the soft segment is typically amorphous with adefined glass transition temperature. The transition temperature of thesoft segment is substantially less than the transition temperature ofthe hard segment in shape memory polymers. A shape in the shape memorypolymer is memorized in the hard and soft segments of the shape memorypolymer by heating and cooling techniques in view of the respectivetransition temperatures as the artisan should appreciate.

Shape memory polymers can be biostable and bioabsorbable. Bioabsorbableshape memory polymers are relatively new and comprise thermoplastic andthermoset materials. Shape memory thermoset materials may includepoly(caprolactone) dimethylacrylates, and shape memory thermoplasticmaterials may include poly (caprolactone) as the soft segment andpoly(glycolide) as the hard segment.

The selection of the bioabsorbable polymeric material used to comprisethe drug delivery device according to the invention is determinedaccording to many factors including, for example, the desired absorptiontimes and physical properties of the bioabsorbable materials, and thegeometry of the drug delivery device.

In order to provide materials having high ductility and toughness, suchas is often required for orthopedic implants, sutures, stents, graftsand other medical applications including drug delivery devices, thebioabsorbable polymeric materials may be modified to form composites orblends thereof. Such composites or blends may be achieved by changingeither the chemical structure of the polymer backbone, or by creatingcomposite structures by blending them with different polymers andplasticizers. Plasticizers such as low molecular weight poly(ethyleneglycol) and poly(caprolactone), and citrate esters can be used. Anyadditional materials used to modify the underlying bioabsorbable polymershould preferably be compatible with the main polymer system. Theadditional materials also tend to depress the glass transitiontemperature of the bioabsorbable polymer, which renders the underlyingpolymer more ductile and less stiff.

As an example of producing a composite or blended material for the drugdelivery device, blending a very stiff polymer such as poly(lacticacid), poly(glycolide) and poly(lactide-co-glycolide) copolymers with asoft and ductile polymer such as poly (caprolactone) and poly(dioxanone)tends to produce a material with high ductility and high stiffness. Anelastomeric co-polymer can also be synthesized from a stiff polymer anda soft polymer in different ratios. For example, poly(glycolide) orpoly(lactide) can be copolymerized with poly(caprolactone) orpoly(dioxanone) to prepare poly(glycolide-co-caprolactone) orpoly(glycolide-co-dioxanone) and poly(lactide-co-caprolactone) orpoly(lactide-co-dioxanone) copolymers. These elastomeric copolymers canthen be blended with stiff materials such as poly(lactide),poly(glycolide) and poly(lactide-co-glycolide) copolymers to produce amaterial with high ductility. Alternatively, terpolymers can also beprepared from different monomers to achieve desired properties.Macromers and other cross-linkable polymer systems can be used toachieve the desired properties. Such properties are conducive to a drugdelivery stent device according to systems and methods of the invention.Of course, the underlying polymer could also be blended with a stifferpolymer to produce a material having stiffer properties, as might beuseful in the case of an orthopedic implant having growth factors orother bio-active agents or drugs delivered therefrom according to thesystems and methods of the invention.

The drugs or other bio-active agents delivered by the drug deliverydevices according to the systems and methods of the invention mayinclude rapamycin, statins and taxol, or any of the other drugs orbio-active agents otherwise identified herein, for example. The drugs orother agents may reduce different indications such as restenosis,vulnerable plaque, angina and ischemic stroke, for example, particularlywhere the device is a stent. Growth factors, such as fibro-blasts andvascular endothelial growth factors can also be used in lieu of, ortogether with, the drugs. Such growth factors may be used forangiogenesis, for example.

In addition to the various drugs identified above, the drugs or otheragents incorporated into the device can also include cytostatic andcytotoxic agents, such as, heparin, sirolimus, everolimus, tacrolimus,biolimus, paclitaxel, statins and cladribine. The various drugs oragents can be hydrophobic or hydrophilic as appropriate. In some of theexamples set forth below, sirolimus was the drug incorporated into thedrug delivery devices.

Other drugs or other bio-active agents usable with the drug deliverydevices made according to the systems and methods described hereininclude: antiproliferative/antimitotic agents including natural productssuch as vinca alkaloids (i.e., vinblastine, vincristine, andvinorelbine), paclitaxel, epidipodophyllotoxins (i.e., etoposide,teniposide), antibiotics (dactinomycin (actinomycinD) daunorubicin,doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins,plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagines); antiplateletagents such as G(GP) 11 _(b)/111 _(a) inhibitors and vitronectinreceptor antagonists; antiproliferative/antimitotic alkylating agentssuch as nitrogen mustards (mechlorethamine, cyclophosphamide and anolgs,melphalan, chlorambucil), ethylenimines and methylmelamines(hexamethylmelamine and thiotepa), alkyl sulfonaates-busulfan,nirtosoureas (carmustine (BCNU) and analogs, streptozocin),trazenes-dacarbazinine (DTIC); antiproliferative/antimitoticantimetabolites such as folic acid analogs (methotrexate), pyrimidineanalogs (flourouracil, floxuridine, and cytarabine), purine analogs andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine {cladribine}); platinum coordination complexes(cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones (i.e., estrogen); anticoagulants (heparin,synthetic heparin salts and other inhibitors of thrombin); fibrinolyticagents (such as tissue plasminogen activator, streptokinase andurokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab;antimigratory; antisecretory (breveldin); anti-inflammatory: such asadrenocortical steroids (cortisol, cortisone, fludrocortisone,prednisone, prednisolone, 6 α-methylprednisolone, triamcinolone,betamethasone, and dexamethasone), non-steroidal agents (salicylic acidderivatives i.e., aspirin; para-aminophenol derivatives i.e.,acetominophen; indole and indene acetic acids (indomethacin, sulindac,and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, andketorolac), arylpropionic acids (tometin, diclofenac, and ketorolac),arylpropionic acids (ibuprofen and derivatives), anthranilic acids(mefenamic acid, and meclofenamic acid), enolic acids (piroxicam,tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, goldcompounds (auranofin, aurothioglucose, gold sodium thiomalate);immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus(rapamycin), azathioprine, mycophenolate (mofetil); angiogenic agents:vascular endothelial growth factor (VEGF), fibroblast growth factor(FGF); angiotensin receptor blockers; nitric oxide donors; anti-senseoligionucleotides and combinations thereof; cell cycle inhibitors, mTORinhibitors, and growth factor receptor signal transduction kinaseinhibitors; retenoids; cyclin/CDK inhibitors; HMG co-enzyme reductaseinhibitors (statins); and protease inhibitors.

The amount of drugs or other agents incorporated within the drugdelivery device according to the systems and methods of the inventioncan range from 0 to 99% (% weight of the device). The drugs or otheragents can be incorporated into the device in different ways. Forexample, the drugs or other agents can be coated onto the device afterthe device has been formed, wherein the coating is comprised ofbioabsorbable polymers into which the drugs or other agents areincorporated. Alternatively, the drugs or other agents can beincorporated into the matrix of bioabsorbable materials comprising thedevice. The drugs or agents incorporated into the matrix ofbioabsorbable polymers can be in an amount the same as, or differentthan, the amount of drugs or agents provided in the coating techniquesdiscussed earlier if desired. These various techniques of incorporatingdrugs or other agents into, or onto, the drug delivery device may alsobe combined to optimize performance of the device, and to help controlthe release of the drugs or other agents from the device.

Where the drug or agent is incorporated into the matrix of bioabsorbablepolymers comprising the device, for example, the drug or agent willrelease by diffusion and during degradation of the device. The amount ofdrug or agent released by diffusion will tend to release for a longerperiod of time than occurs using coating techniques, and can often moreeffectively treat local and diffuse lesions or conditions therefore. Forregional drug or agent delivery such diffusion release of the drugs oragents is effective as well.

The drug delivery device according to the systems and methods of theinvention preferably retains its mechanical integrity during the activedrug delivery phase of the device. After drug delivery is achieved, thestructure of the device ideally disappears as a result of thebioabsorption of the materials comprising the device. The bioabsorbablematerials comprising the drug delivery device are preferablybiocompatible with the tissue in which the device is implanted such thattissue interaction with the device is minimized even after the device isdeployed within the patient. Minimal inflammation of the tissue in whichthe device is deployed is likewise preferred even as degradation of thebioabsorbable materials of the device occurs.

Because visualization of the drug delivery device as it is implanted inthe patient is helpful to the medical practitioner for locating andorienting the device, and for maximizing the dispersal of the drugs orother agents to an intended site once implanted, radiopaque materialsmay be added to the device. The radiopaque materials may be addeddirectly to the matrix of bioabsorbable materials comprising the deviceduring processing thereof, resulting in fairly uniform incorporation ofthe radiopaque materials throughout the device. Alternatively, theradiopaque materials may be added to the device in the form of a layer,a coating, a band or powder at designated portions of the device,depending on the geometry of the device and the process used to form thedevice.

Ideally, the radiopaque material does not add significant stiffness tothe drug delivery device so that the device can readily traverse theanatomy within which it is deployed. The radiopaque material should bebiocompatible with the tissue within which the device is deployed. Suchbiocompatibility minimizes the likelihood of undesirable tissuereactions with the device. Inert noble metals such as gold, platinum,iridium, palladium, and rhodium are well-recognized biocompatibleradiopaque materials. Other radiopaque materials include barium sulfate(BaSO₄), bismuth subcarbonate ((BiO)₂CO₃), bismuth oxide, tungsten,tantalum, and iodine compounds, at least some of which are used inexamples described further below. Ideally, the radiopaque materialsadhere well to the device such that peeling or delamination of theradiopaque material from the device is minimized, or ideally does notoccur.

Where the radiopaque materials are added to the device as metal bands,the metal bands may be crimped at designated sections of the device.Alternatively, designated sections of the device may be coated with aradiopaque metal powder, whereas other portions of the device are freefrom the metal powder. As the artisan should appreciate, barium is mostoften used as the metallic element for visualizing the device usingthese techniques, although tungsten and other fillers are also becomingmore prevalent.

Radiopaque coatings on all or portions of the device can also be used toenhance the radiopacity and visualization of the device deployed withinthe patient. Such coatings sometimes have less negative impact on thephysical characteristics (eg., size, weight, stiffness, flexibility) andperformance of the device than do other techniques. Coatings can beapplied to the device in a variety of processes known in the art suchas, for example, chemical vapor deposition (CVD), physical vapordeposition (PVD), electroplating, high-vacuum deposition process,microfusion, spray coating, dip coating, electrostatic coating, or othersurface coating or modification techniques.

Alternatively, the bioabsorbable polymer materials used to comprise thedrug delivery device according to the invention can include radiopaqueadditives added directly thereto during processing of the matrix of thebioabsorbable polymer materials to enhance the radiopacity of thedevice. The radiopaque additives can include inorganic fillers, such asbarium sulfate, bismuth subcarbonate, bismuth oxides and/or iodinecompounds. The radiopaque additives can instead include metal powderssuch as tantalum or gold, or metal alloys having gold, platinum,iridium, palladium, rhodium, a combination thereof, or other materialsknown in the art. The particle size of the radiopaque materials canrange from nanometers to microns, and the amount of radiopaque materialscan range from 0-99% (wt %).

Because the density of the radiopaque additives is typically very highwhere the radiopaque materials are distributed throughout the matrix ofbioabsorbable materials, dispersion techniques are preferably employedto distribute the radiopaque additives throughout the bioabsorbablematerials as desired. Such techniques include high shear mixing,surfactant and lubricant additions, viscosity control, surfacemodification of the additive, and other particle size, shape anddistribution techniques. In this regard, it is noted that the radiopaquematerials can be either uniformly distributed throughout thebioabsorbable materials of the device, or can be concentrated insections of the device so as to appear as markers similar to asdescribed above.

Preferred low temperature processes of forming the drug delivery devicesaccording to the systems and methods of the invention include solutionprocessing and supercritical fluid processing techniques. Theseprocesses include solvent extraction, coating, wire-coating, extrusion,co-extrusion, fiber-spinning including electrostatic fiber-spinning,lyophilization and other techniques that incorporate drugs or otherbio-active agents that are unstable at high temperatures into the matrixof bioabsorbable polymeric materials that will comprise the drugdelivery device. For drugs or agents that are stable at hightemperature, different melt processing techniques may instead be used toincorporate the drugs or agents into the matrix of bioabsorbablepolymers that comprise the device. Alternatively, the drugs or agentsmay be sprayed, dipped, or coated onto the device after formationthereof from the bioabsorbable polymers. In either case, the polymermatrix, and drug or agent blend when provided, is then converted into astructure such as fibers, films, discs/rings or tubes, for example, thatis thereafter further manipulated into various geometries orconfigurations as desired.

Different processes can thus provide different structures, geometries orconfigurations to the bioabsorbable polymer being processed. Forexample, tubes processed from rigid polymers tend to be very stiff, butcan be very flexible when processed via electrostatic processing orlyophilization. In the former case, the tubes are solid, whereas in thelatter case, the tubes are porous. Other processes provide additionalgeometries and structures that may include fibers, microfibers, thin andthick films, discs, foams, microspheres and even more intricategeometries or configurations. Melt or solution spun fibers, films andtubes can be further processed into different designs such as tubular,slide and lock, helical or otherwise by braiding and/or laser cutting.The differences in structures, geometries or configurations provided bythe different processes are useful for preparing different drug deliverydevices with desired dimensions, strengths, drug delivery andvisualization characteristics.

Different processes can likewise alter the morphological characteristicsof the bioabsorbable polymer being processed. For example, when dilutesolutions of polymers are stirred rapidly, the polymers tend to exhibitpolymer chains that are generally parallel to the overall axis of thestructure. On the other hand, when a polymer is sheared and quenched toa thermally stable condition, the polymer chains tend to elongateparallel to the shear direction. Still other morphological changes tendto occur according to other processing techniques. Such changes mayinclude, for example, spherulite to fibril transformation, polymorphiccrystal formation change, re-orientation of already formed crystallinelamellae, formation of oriented crystallites, orientation of amorphouspolymer chains and/or combinations thereof.

In the case of a drug delivery device comprised of bioabsorbablepolymeric materials according to the systems and method of theinvention, the device may be formed by solution spinning fibers orsolvent cast films or tubes, for example, wherein the polymer fibers,films or tubes are typically formed at ambient conditions. As a result,drugs incorporated therein the bioabsorbable polymeric materials do notdegrade as readily. After formation, the fibers, films or tubes arelaser cut to a desired geometry or configuration such as in the shape ofa stent, for example, including a helical pattern as shown in FIGS. 1thru 3.

The helical stent can be a solid ladder pattern 1 a as shown in FIG. 1,or can be more of an open lattice pattern 2 as shown in FIG. 2. Hybrids3 a of a solid ladder pattern with an open lattice pattern can alsocomprise the stent, as in FIG. 3, if desired.

As discussed in greater detail further below, FIG. 1 illustrates thesolid ladder stent 1 a in a deployed state, in a balloon mounted state 1b, and in a precursor film state 1 c from which the stent is made. FIG.3 likewise illustrates the hybrid stent 3 a in a deployed state 3 a, ina balloon mounted state 3 b, and in a film precursor state 3 c. Althoughnot shown, the open lattice stent 2 is understood to have similardeployed, balloon mounted and precursor film states according to thesystems and methods of the invention. In either case, the stent iscomprised of bioabsorbable polymeric materials into, or onto, whichdrugs or other bio-active agents and/or radiopaque additives arecombined during the processing thereof, as described in more detail inthe Examples set forth below. After formation of the bioabsorbablepolymeric materials into a tube, film, fiber or other structure with thedrugs, agents and/or radiopaque materials incorporated therein orthereon, the tubes, films, fibers or other structures can be laser cut,braided or otherwise worked into the helical stent or other geometry toform the drug delivery device as desired. Of course, the device mayinstead be worked into a non-stent device comprised of a ring, or wrap,FIGS. 4 a-4 c, for example, wherein the drugs or other agents andradiopaque markers are incorporated into or onto the bioabsorbablematerials forming the device. FIG. 4 a shows a ring 4 a with a slit (s)enabling the ring 4 a to be fitted over a vessel, for example, whereasFIG. 4 b shows a pair of semicircular wraps 4 b that may be suturedtogether around a vessel, and FIG. 4 c shows a cylinder 4 c with a slit(s) enabling the cylinder 4 c to be fitted over a vessel.

In the case of helical shaped stents comprised of bioabsorbablepolymeric materials and drugs or other agents, and/or radiopaquematerials as desired, a preferred process of making such stents issolvent casting. For example, the bioabsorbable polymeric materials andadditives are solvent cast into a film, cut into strips of desiredlengths, laser cut into the helical coil or other design, and mountedand wound onto a heated mandrel to provide a desired interior diameter.The strips can be converted to lower profiles, i.e., having smallerinterior diameters, by winding them on a mandrel with a smaller outerdiameter. The wound strip is then mounted onto a balloon catheter andheat nested in a nesting tube to attach the wound strip to the balloon(FIGS. 1 b and 3 b). During balloon inflation, the wound strip detachesfrom the balloon and expands to form a deployed stent as shown in FIGS.1 a and 3 a. The final size of the deployed stent depends on severalvariables such as interior diameter of the wound strip, interiordiameter of the nesting tube, balloon length and expanded outerdiameter, and stent material. The radial strength of helical stents madein this manner varies depending on the design (solid ladder, openlattice, or hybrid), wall thickness of the stents, and materials used tocomprise the stents. Stiffer polymers such as PLLA and PLGA tend to havethe highest radial strength, whereas elastomeric polymers such asPCL/PGA (35/65) tend to have lower radial strength characteristics. Thestents can be formed with different materials, as described above, in amanner as described further in Examples set forth below, and can bedelivered percutaneously using conventional balloon and self expandingdelivery systems. The absorption profile of the stent can be tailored toclinical needs such that drug delivery can occur locally or regionallyover designated time periods.

FIG. 5 a illustrates a film strip 10 from which a solid ladder stent,such as stent 1 a of FIG. 1, is made. The film strip 10 is cut from filmprepared by solvent cast film methods, for example, or by other methodsas described herein. The dimensions shown in FIG. 5 a are exemplary onlyand are understood to be alterable to suit various medical needs.

In FIG. 5 a, the film strip 10 has been cut into approximately 2 mm wide(w) strips of approximately 30 mm in length (l). The film strip 10 isgenerally comprised of a first pair of opposed sides 12 a and 12 b, anda second pair of opposed sides 11 a and 11 b, wherein opposed sides 12 aand 12 b are longer than opposed sides 11 a and 11 b. The sides 11 a and11 b are cut at angles (α) approximately 10-30 degrees, and preferably20 degrees, relative to a respective side 12 a and 12 b. The helicalaxis pitch (P) is approximately 4.0 mm in FIG. 5, and the helical screwpitch length (SPL) is approximately 12 mm. In the case of a solid ladderstent fabricated from the strip 10 of FIG. 5 a, alternating struts arenot provided in the film strip 10, so as to form the solid portions ofthe solid ladder stent 1 a, for example. In practice, the film strips 10are coiled about a heated mandrel, shaped and cooled into the desiredhelical structure as shown in FIG. 1 a, for example. Alternatively, andpreferably, the film strip 10 is coiled about a mandrel in the presenceof heat, shaped and cooled into the helical structure shown in FIG. 5 b,wherein sides 11 a and 11 b are squared ends that are blunter than thoseshown in the deployed stent 1 a shown in FIG. 1. The squared ends ofsides 11 a and 11 b result from the angle α as described above. Forexample, the sides 11 a and 11 b in FIG. 5 b do not flare out as much asthose ends shown in FIG. 1 a.

The interior diameter of the stent is determined by the outer diameterof the mandrel on which the film strip 10 is coiled. Cutting the sides11 a and 11 b of the stent at angles α provides improved fluid flowthrough the lumen of the stent, whereby an angle α of 20 degreesprovides even more uniform and less turbulent fluid flow through thestent. Such contributes to improved endothelialization and tissuehealing with respect to the vessel, or other passageway, in which thestent is implanted. Of course, the artisan will appreciate that the filmstrips can be cut into other shapes and geometries as desired.

FIG. 6 a illustrates a film strip 20 from which an open lattice stent,such as stent 2 of FIG. 2 is made, the film strip 20 having been cutfrom film prepared by solvent cast film methods, or other methods asdescribed herein. The dimensions shown in FIG. 6 a are exemplary onlyand are understood to be alterable to suit various medical needs. InFIG. 6 a, the film has been cut into approximately 2 mm wide (w) stripsof approximately 30 mm in length (l), and includes pairs of opposedsides 22 a and 22 b, and 21 a and 21 b, similar to as described withrespect to FIG. 5 a. The opposed sides 21 a and 21 b are cut at angles αof approximately 10-30 degrees, and preferably 20 degrees, relative to arespective side 22 a and 22 b, and the helical axis pitch (P) isapproximately 4.0 mm. The helical screw pitch length (SPL) isapproximately 12 mm. Approximately four alternating struts 23 areincluded per SPL cycle in order to form the open lattice helical stentas in FIG. 2.

Referring still to FIG. 6 a, the interior diameter of the stent isdetermined by the outer diameter of the mandrel on which the film strip20 is coiled. Cutting the sides 21 a and 21 b of the stent at angles αprovides improved fluid flow through the lumen of the stent, whereby anangle α of 20 degrees provides even more uniform and less turbulentfluid flow through the stent. This is mainly because, referring to FIG.6 b, the stents with sides 21 a and 21 b at such 20 degree anglesprovide blunt, or squared, ends (sides 21 a, 21 b) as shown in FIG. 6 b.The bluntness of sides 21 a, 21 b in FIG. 6 b (only side 21 b shown inFIG. 6 b) differs from the generally flared out ends of the deployedstent 2 of FIG. 2, for example, or more generally any of the deployedstents depicted in FIGS. 1-3. Such contributes to improvedendothelialization and tissue healing with respect to the vessel, orother passageway, in which the stent is emplaced. The stent as shown inFIGS. 6 a-6 b also has been found in animal studies to provide improvedregional drug diffusion and tissue uptake of the drug even beyondproximal and distal ends of the stent when emplaced in the animal. FIGS.9 and 10 are graphs illustrating such drug diffusion andpharmacokinetics along these lines. Of course, the artisan willappreciate that the film strips can be cut into other shapes andgeometries as desired.

Although not shown, hybrid stents such as those shown in FIG. 3 aresimilarly made using combinations of the methods, dimensions andgeometries of FIGS. 5 a and 6 b, as should be readily evident to theartisan.

Examples I-III, set forth below, describe the production of solvent castfilms to comprise a drug delivery device according to the invention,wherein the devices are comprised of bioabsorbable polymeric materialscomprised of polylactide/polyglycolide copolymers such as PLA/PGA (95/5and 85/15), and blends thereof. Blends were prepared to make stiffpolymers more ductile and flexible in order to prepare stents thatrequire more strain values. Different solvents were used to prepare thefilms such as chloroform, dioxane, and binary solvent mixtures such asdioxane/acetone and dioxane/ethyl acetate. Different radiopaque agentswere used from 10 to 40% (by weight) from materials including bariumsulfate, bismuth subcarbonate, and bismuth oxide. Sirolimus was used asthe drug in these films from 5 to 30% (by weight).

FIG. 7 shows a typical film fabrication process. Polymer resins areadded to a given solvent and tumbled with or without heat until thepolymer dissolves completely in the solvent to provide a homogenoussolution. Polymer formulations can be prepared using these solutionsthat may include radiopaque agents, drug or combinations thereof. Theseformulations are tumbled and mixed properly in order to prepare uniformdispersions. These formulations can be converted to films by pouringthem in a mold on to a glass plate and allowing the solvent to evaporateovernight in a nitrogen rich environment at room temperature. The filmmay be removed from the glass plate and the solvent can be furtherremoved under conditions including high temperature oven drying (e.g.,110° C. for 10 hours), low temperature oven drying (e.g., 25° C. to 60°C. for 6 hours), low temperature carbon dioxide extraction (e.g., 40° C.at 60 to 80 bar pressure for 20 to 60 minutes), lyophilization andcombination thereof. Low temperature drying is used to preserve drugcontent in the films. The drying conditions will also determine themorphology (amorphous or crystalline) of the films. After drying, thefilms can then be stored in an inert environment (nitrogen box) untilfurther testing and prototyping.

EXAMPLE I Polymer with Drug/Agent

Preparation of PLA/PGA 95/5 Films with Sirolimus from Chloroform

PLA/PGA 95/5 resin was obtained from Purac Inc., with an intrinsicviscosity of about 2.2.

A summary of a film making protocol is given below:

Prepare PLA/PGA stock solution at 4.3% by weight by dissolving PLA/PGAin chloroform and tumbling the solution overnight at room temperature.

Add sirolimus in desired amounts of 0 to 30% to the stock solution.

Pour a predetermined mass of the PLA/PGA and drug into a mold positionedin the center of a glass plate (12″ by 12″).

Cover the mold to reduce the rate of chloroform evaporation.

Slowly dry the films overnight at room temperature in a nitrogen richenvironment.

Release the films from the glass plates.

Dry further to remove residual solvent under different conditions asdescribed above.

Other post treatment of the films including annealing and orientation atdifferent temperatures can be performed.

Cut the film into strips as desired and store until needed.

Thereafter, the film strips may be laser cut into desired shapes andgeometries, including the helical solid ladder, open lattice or hybridsthereof described above.

Prior to cutting the films into 2 mm wide strips, for example, the filmuniformity was verified by measuring film thickness in five regions,i.e, at each corner and at the center of each film. In general, filmthickness averaged 150 microns among all samples with a maximumthickness of 220 microns in the films containing 30% sirolimus.

EXAMPLE II Polymer with Drugs/Agents and Radiopaque Material

Preparation of PLA/PGA (95/5) Films with Sirolimus and Radiopaque Agents

PLA/PGA 95/5 and 85/15 resins were obtained from Purac Inc., with anintrinsic viscosity of about 2.2 and 2.3, respectively. Barium sulfateof different particle size (1 and 0.1 microns) was obtained from ReadeAdvanced Material and Sachtleben Corporation. Bismuth subcarbonate andbismuth oxide were obtained from Spectrum and Nanophase TechnologiesCorporation, respectively.

In general, the radiopaque agents are added after the preparation of thePLA/PGA stock solution prepared above as in Example I. The formation ofthe films then generally continues as otherwise set forth in Example Iexcept as otherwise detailed herein with respect to the variousradiopaque agents. The radiopaque agents may be barium sulfate orbismuth subcarbonate. The radiopaque agents are added to the PLA/PGAsolution by sonication, by high speed mixing, or by tumbling. Sonicationwas found to more effectively disperse barium sulfate in the stocksolution than it did bismuth subcarbonate. The PLA/PGA stock solutionwas 12% (by weight). Preparation of films containing specific radiopaqueagents in varying concentrations are detailed further below.Super-critical fluids could also be used to remove any residual solvent.

a. Preparation of PLA/PGA (95/5) Films Containing Barium Sulfate (BlancFixe XR-HN, Particle Size 1 Micron)

Solutions containing 10%, 20% and 30% by weight barium sulfate (based ontotal solids) as the radiopaque agent and a fixed level of sirolimus(15% w/w, based on drug and polymer) were prepared in the followingmanner:

Prepare PLA/PGA stock solution at 15.0% by weight. Dissolve target massof PLA/PGA in chloroform and tumble the solution overnight at roomtemperature

Weigh target mass of barium sulfate in an amber bottle.

Weigh target mass of chloroform into the same amber bottle.

Sonicate the barium sulfate in chloroform for 20 minutes.

Weigh target mass of sirolimus into a pre-cleaned amber bottle.

Weigh PLA/PGA stock solution into sirolimus containing bottle.

Add barium sulfate dispersion to the PLA/PGA stock solution.

Purge any air gap with nitrogen gas and seal the bottle.

Tumble complete formulation overnight.

Filter through stainless steel mesh (25 micron hole size) to removelarger particles.

Weigh desired mass of solution (about 90 g is required to cast a film)into three separate jars.

Let stand at room temperature for a minimum of 1 hour to remove bubbles.Gently swirl for about 3 minutes.

Pour the solution into the mold and re-weigh the jar after the transfer.The difference in mass represents the mass of coating solution used toprepare the film.

Release the film from glass plate and dry the film as described above.

Place the dried films in a box purged with nitrogen for storage.

Thereafter the films can be laser cut or otherwise worked into a desiredgeometry and stored until needed.

A summary of the weights used to prepare the three coatings solutionsincluding various concentrations of barium sulfate (XR-HN), based on atarget mass of about 200 g, is provided immediately below.

Compositions of Solutions Used to Prepare Films Target Loading (% w/w)of Barium Sulfate (Blanc Fixe XR-HN) Reagent 10% 20% 30% Barium sulfate(g) 1.12 2.51 4.28 Chloroform (g) 143.98 142.80 140.23 Sirolimus (g)1.5127 1.5165 1.5163 PLA/PGA, (14.99% w/w) 56.60 57.01 56.71 Total mass(g) 203.21 203.84 202.74 Actual BaSO₄ content (%) 10.1 20.0 29.9 ActualSirolimus content 15.14 15.07 15.14 (%)

Different grades and particle size (e.g., 0.1 micron) of barium sulfatecan be used to prepare similar formulations.

b. Preparation of PLA/PGA Films Containing Bismuth Subcarbonate

Solutions containing 10%, 20% and 30% by weight bismuth subcarbonate(particle size of about 9 microns) and a fixed amount of sirolimus (15%w/w) were prepared using a slightly modified procedure than as describedabove for other radiopaque agent films. Films containing dispersedbismuth subcarbonate contained a greater fraction of larger particlesthan films loaded with barium sulfate. As a result, the salt containingPLA/PGA solution was tumbled for a longer period of time (3 days) toallow the shearing action of the polymer to assist in breaking upagglomerated salt particles.

After 3 days of tumbling, sirolimus drug was added directly into theamber bottles containing the salt and polymer dissolved in chloroform.The complete procedure to prepare the formulations and films weresimilar to that described above.

c. Preparation of PLA/PGA (85/15) Films Containing Bismuth Oxide asRadiopaque Agents from Dioxane:

Bismuth oxide was evaluated in powder form as well as in pre-dispersedform in dioxane. The target compositions are shown below:

PLA-PGA (85:15) containing 20% bismuth oxide (NanoArc™) cast fromstabilized dioxane

PLA-PGA (85:15) containing 20% bismuth oxide predispersed (NanoTek®) indioxane

PLA-PGA (85:15) containing 30% bismuth oxide cast from stabilizeddioxane

The bismuth oxide predispersion in dioxane (bismuth oxide in 1,4-dioxaneat 19.8 wt %) contained dispersing agents at 1-3% by weight. In filmform, these dispersants contribute significantly to the overallcomposition of the film.

The steps used to formulate the three casting dispersions are describedbelow:

A parent PLA-PGA (85:15) solution in dioxane was prepared at 8.50% byweight.

A parent bismuth oxide dispersion was prepared. This dispersion was usedto formulate dispersions containing 20% and 30% bismuth oxide, on atotal solids basis.

Part of the parent dispersion was reduced with dioxane to produce thedispersion with 30% bismuth oxide, on a total solids basis.

Another portion of the parent dispersion was reduced with dioxane andthe parent polymer solution (8.5% w/w) to achieve 20% bismuth oxide.

A known mass of the bismuth oxide dispersion (19.8% w/w) was added to aPLA-PGA solution at 6.50% by weight to prepare the dispersion containing20% bismuth oxide.

Of course, drugs or other bioactive may be incorporated herein as inother described examples.

Preparation of Parent Casting Dispersion

A 1″ tubular mixing assembly was used for preparing dispersions. Thesteps used to make up the dispersions are summarized below:

Weigh and add the target mass of stabilized dioxane into a clear widemouth jar (500 mL capacity).

Weigh and add a portion of the 8.5% w/w PLA-PGA solution, (about 12% oftarget mass to be added) into the same jar.

Position the mixing head just above the base of the jar and screw thecap tightly. Mix at 10,000 rpm. The polymer helps disperse the bismuthoxide and minimizes splatter on the walls.

Slowly add the target mass of bismuth oxide into the jar under highagitation (10,000 rpm) using a funnel over a period of 3 to 5 minutes.Disperse the mixture at 10,000 rpm for 7 minutes.

Pour the remainder of the polymer solution (8.5% w/w) into the jar underagitation and mix for an additional 5 minutes.

Filter the dispersion through a 25 micron pore size mesh using a 50 mLglass syringe fitted with a stainless steel filtration housing.

Films were prepared from these three dispersions by pouring them in tothe molds as described earlier. In this case, the films were dried at110° C. for 12 hours.

In general, the surface of the films is relatively smooth with nonoticeable agglomerates or surface imperfections. The film prepared frombismuth oxide predispersed in dioxane appears to be the smoothest of thethree film types. The average film thickness was about 120 microns.

Similar films were prepared from other contrast agents such as iodinecompounds, tungsten, and tantalum.

d. Preparation of PLA/PGA (95/5 and 85/15) Films Containing BariumSulfate as Radiopaque Agents from Dioxane and Chloroform:

PLA-PGA Films from Dioxane:

PLA-PGA casting solutions were prepared in dioxane. Films were preparedby pouring the solution into a clear wide-mouth jar and let the castingsolution stand at room temperature for about 30 minutes to allow bubblesto escape. Gently swirl the dispersion for about 2 minutes and pour intothe mold. Pour casting solutions with or without barium sulfate directlyinto the mold. Place a cover over the mold and purge the atmosphereabove the film with nitrogen.

The films were dried at room temperature for 18 hours followed by 45° C.drying for 18 hours. The films were dried at 110° C. for 10 hours. Thedried films had 20% barium sulfate by weight.

The three most uniform strips from each film were selected formechanical testing. The measurements were performed in accordance withthe test method described in ASTM D 882-02, “Tensile Properties of ThinPlastic Sheeting” using an Instron tensile tester at 23±2° C. and 50±5%R.H.

A summary of the mechanical properties of the PLA/PGA films reported asan average over three test specimens is given in Table I below. PurePLA-PGA films as well as films containing barium sulfate were tested. Ofcourse, drugs or bioactive may be added as in earlier describedexamples. In general, films prepared from the two grades (95:5 and85:15) of PLA-PGA displayed similar physical properties.

The pure PLA-PGA films had elongation values in the 2% to 4% range, forboth grades of PLA-PGA. The addition of barium sulfate lowers elongationvalues by about 10% to 15%. The addition of barium sulfate did notchange the general appearance of the stress/strain curves.

TABLE I Tensile Properties of PLA-PGA Films Cast from Dioxane Stress atStrain at Stress at Strain at Yield Yield Modulus Break Break Sample(MPa) (%) (Mpa) (MPa) (%) Toughnes (MPa) PLA-PGA (85:15) Series Pure85:15 68.8 3.03 4092 65.12 4.55 9.97 85:15 with BaSO₄ 62.9 2.74 438058.10 3.79 11.45 PLA-PGA (95:5) Series Pure 95:5 70.9 3.79 2905 66.54.42 20.5 95:5 with BaSO₄ 57.7 3.04 3766 50.8 4.08 18.3 *Strain at yieldand strain at break as well as the modulus were calculated based on gripseparation and not extensometer values.

The modulus of the films was calculated using the segment modulusbetween 0.5% and 1.5% strain by grip separation. The specific limitsselected to determine the modulus vary somewhat from film to film.

Other films were made from various PLA-PGA polymer blends in thepresence of a chloroform solvent. These solutions and films wereotherwise prepared the same way as described above using the solventdioxane. Again, drugs or other bioactive agents may be added as inearlier described examples.

A summary of the mechanical properties of the PLA-PGA/chloroform filmsreported as an average over at least three test specimens is given inTable II below. Pure PLA-PGA films as well as films containing bariumsulfate were tested.

TABLE II Tensile Properties of PLA-PGA Films Cast from Chloroform StressStrain at Stress at Strain at Sample at Yield Yield Modulus Break BreakI.D. (MPa) (%) (Mpa) (MPa) (%) Toughness (MPa) PLA-PGA (85:15) SeriesPure 85:15 65.4 3.0 4119 62.3 3.5 9.0 85:15 with BaSO₄ 60.4 3.1 284355.8 3.9 12.1 PLA-PGA (95:5) Series Pure 95:5 74.1 3.4 3690 63.7 9.8 8.895:5 with BaSO₄ 66.1 3.8 3311 58.7 8.2 13.4 *Strain at yield and strainat break as well as the modulus were calculated based on grip separationand not extensometer values.

In general, films prepared from the two grades (95:5 and 85:15) ofPLA-PGA displayed similar physical properties:

EXAMPLE III

Preparation of Polymer Films with Barium Sulfate Using Solvent BinaryMixtures

The materials used throughout Example III are summarized below. PLA/PGA85/15 and 95/5 were obtained from Purac Inc., with an intrinsicviscosity of about 2.2 and 2.3, respectively. Barium sulfate wasobtained from Reade Advanced Material.

Preparation of Casting Solutions

Pure PLA-PGA Casting Solutions

Four pure polymer casting solutions were prepared, two using the 95:5grade PLA/PGA and two using the 85:15 grade PLA-PGA as shown below:

PLA-PGA (95:5) dissolved in a 50:50 w/w % mixture of dioxane/acetone anddioxane/ethyl acetate.

PLA-PGA (85:15) dissolved in a 25:75 w/w % mixture of dioxane/acetoneand dioxane/ethyl acetate.

The table below summarizes the weights used to prepare the castingsolutions.

Composition of Barium Sulfate-Containing Casting Dispersions % by Weightof Ingredient Different Ingredients Barium sulfate 1.39 1.41 PLA-PGA(85:15) 5.03 5.01 Dioxane:acetone (25:75 w/w %) 93.58 — Dioxane:ethylacetate (25:75 w/w %) — 93.58 Target mass (g) of casting solution 66 66poured into rectangular (5 × 7 in²) mold Barium sulfate 1.16 1.14PLA-PGA (95:5) 4.04 4.04 Dioxane:acetone (50:50 w/w %) 94.80 —Dioxane:ethyl acetate (50:50 w/w %) — 94.82 Target mass (g) of castingsolution 83 82 poured into rectangular (5 × 7 in²) mold

Films were prepared from these dispersions as described earlier and weredried at 110° C. for 12 hours to remove residual solvents.

Drugs or other bioactive agents may be added as in earlier describedexamples.

A summary of the mechanical properties of the PLA-PGA film blends isreported as an average of at least three test specimens in the Table IIIbelow.

In general, films cast from PLA-PGA (85:15) were of better quality thanfilms prepared from the 95:5 grade of the polymer regardless of thesolvent mixture.

In general, films prepared from the different solvent mixtures displayedsimilar physical properties.

Films prepared using the 85:15 grade of PLA-PGA cast from 25:75 mixturesof dioxane:acetone or dioxane:ethyl acetate displayed elongation valuesof 3.5%, with good agreement between specimens (standard deviations ofless than 6%). The solvent mixture used to dissolve the polymer hadlittle, if any, influence on elongation values. The addition of bariumsulfate also had no influence on elongation values.

Films prepared using the (95:5) grade of PLA-PGA cast from 50:50mixtures of dioxane:acetone or dioxane:ethyl acetate displayedelongation values of 2.7%, with better than expected agreement betweenfilms specimens (standard deviations of less than 10%).

Stress at yield values changed very little for these films. The valuesranged from 53 to 58 MPa for the 95:5 grade of PLA-PGA and remainedessentially unchanged (65 MPa) for the 85:15 of the copolymer. Thesevalues were very similar to the stress at break values.

Strain at yield values also changed very little ranging from 2.6 to 3.7%and from 3.2 to 3.5% for the 95:5 and 85:15 grades of PLA-PGA,respectively.

Modulus values did not follow any trend with solvent mixture or additionof barium sulfate. Values ranged from 3423 to 5870 MPa and from 4000 to5294 MPa for the 95:5 and 85:15 grades of PLA-PGA, respectively. Asimilar trend was observed for the 95:5 grade of polymer with stress atyield values dropping from 74 to 58 MPa and modulus values from 3690 to2938 MPa.

TABLE III Tensile Properties of PLA-PGA Films Cast from Binary SolventMixtures Stress at Strain at Stress at Sample Yield Yield Modulus BreakStrain at Break I.D. (MPa) (%) (MPa) (MPa) (%) Toughness (MPa) PLA-PGA(95:5) in 50:50 mixtures of dioxane (D) with acetone (A) or ethylacetate (EA) Pure 95:5 in D:A 53.0 2.6 3676 53.0 2.6 3.9 Pure 95:5 inD:EA 56.3 2.8 4430 56.2 2.8 4.8 With BaSO₄ in D:A 57.5 3.4 5870 56.4 3.74.9 With BaSO₄ in D:EA 57.6 3.7 3423 57.0 3.9 7.7 PLA-PGA (85:15) in25:75 mixtures of dioxane (D) with acetone (A) or ethyl acetate (EA)Pure 85:15 in D:A 64.6 3.5 3998 64.2 3.6 5.9 Pure BaSO₄ D:EA 64.2 3.34142 63.5 3.5 7.0 With BaSO₄ in D:A 66.2 3.2 5226 63.9 3.4 6.0 WithBaSO₄ in D:EA 65.2 3.2 5294 63.1 3.5 9.1 *Strain at yield and strain atbreak as well as the modulus were calculated based on grip separationand not extensometer values.

The modulus of the films was calculated using the segment modulusbetween 0.5% and 1.5% strain by grip separation. The specific limitsselected to determine the modulus varied somewhat from film to film.

In general, the drug delivery device stents of Examples I-III wereprepared with dioxane, chloroform or other solvents and differentamounts of sirolimus (0-30%) and radiopaque agents (0-30%) havingdifferent particle sizes (0.1-10 microns). The films were prepared fromPLGA 95/5 and PLGA 85/15. Once prepared, the films were laser cut intodifferent lengths and geometries, i.e., solid ladder, open lattice &hybrid, wound on a mandrel at temperatures above the glass transitiontemperature of the polymers and then mounted onto balloon catheters anddeployed in a water bath at 37° C. The solid ladder devices, with about30% radiopaque agents, exhibited the greatest visibility, whereas theopen lattice stents exhibited the lower visibility due to lesser mass ofthe open lattice stents. Referring back to FIG. 1, a solid ladder PLGA95/5 stent 1 a with 20% barium sulfate and 15% sirolimus is shown asballoon mounted 1 b, and in its cut length 1 c from the prepared film.The cut length 1 c of the stent is 30 mm, the balloon mounted length 1 bof the stent is about 20 mm, and the length of the deployed stent 1 a is18 mm. FIG. 3 a-c shows similar length changes for the hybrid stent 3 ain its film cut length 3 c, its balloon mounted length 3 b, and itsdeployed state 3 a. The radial strength for the solid ladder stent 1 ain FIG. 1 a was about 20 to 25 psi, and the radial strength for thehybrid stent 3 a of FIG. 3 a was about 10 to 15 psi. The radial strengthcan be varied using amorphous or crystalline morphology, whereinamorphous stents will tend to have lower properties than crystallinestents.

As mentioned at different times herein, the bioabsorbable polymericsolution serving as the foundation of the film from which the drugdelivery device will be cut from can be a blend of polymers as well asset forth in Example IV below.

EXAMPLE IV

(a) Preparation of Films for Polymer Blend Evaluation

The intrinsic viscosity of PCL-PDO (95:5) and PGA-PCL (65:35) used inthis study was about 1.5 and 1.4, respectively.

Films were cast in rectangular molds and dried in the original(single-sided) configuration. Films were dried first at 45° C. for 18hours and then at 110° C. for 10 hours.

The solubility of the two softer copolymers in dioxane was assessedbefore preparation of the polymer blends. Solutions of PCL-PDO (95:5)and PGA-PCL (65:35) were prepared at a concentration of 6% by weight.The two solutions were first tumbled (7 revolutions/min) at roomtemperature overnight. After 24 h, PCL-PDO was completely dissolvedwhile the PGA-PCL solution still contained free flowing granules. Thissolution was tumbled (5 revolutions/min) in an oven set at 60° C. After1 hour of tumbling no granules remained.

The PGA-PCL solution was less viscous than PCL-PDO, which is lessviscous than PLA-PGA (95:5) in dioxane at 6% by weight solids.

Pure films were prepared from PCL-PDO (95:5) as well as PGA-PCL (65:35)in dioxane. PGA-PCL formed a soft clear slightly brownish film whilePCL-PDO formed an opaque and more brittle film.

The steps used to prepare the eight casting solutions (see Tables IV andV) are summarized below:

Blends of PLA-PGA (95:5) with 5%, 10%, 15% and 20% PGA-PCL (65:35)

Weigh and add target mass of PLA-PGA into amber bottle. Next weigh andadd target mass of PGA-PCL into amber bottle. The final polymer solidscontent was 6% w/w in dioxane.

Weigh and add the target mass of dioxane directly into amber bottlecontaining polymer.

Purge head-space with nitrogen gas and seal bottle. Tumble overnight(rotational speed=5/min) at 60±2° C.

Blends of PLA-PGA (95:5) with 5%, 10%, 15% and 20% PCL-PDO (95:5)

Repeat the same procedure for preparing blends of PLA-PGA (95:5) with5%, 10%, 15% and 20% PCL-PDO (95:5).

TABLE IV Composition of Casting Solutions Used to PreparePLA-PGA/PGA-PCL Blends Ingredient Mass (g) Composition (% w/w) SampleNumber 1 PLA-PGA (95:5) 11.41 5.70 PGA-PCL (65:35) 0.60 0.30 Dioxane*(g) 188.10 94.00 Sample Number 2 PLA-PGA (95:5) 10.80 5.40 PGA-PCL(65:35) 1.21 0.60 Dioxane 188.00 94.00 Sample Number 3 PLA-PGA (95:5)10.19 5.09 PGA-PCL (65:35) 1.84 0.92 Dioxane 188.08 93.99 Sample Number4 PLA-PGA (95:5) 9.60 4.80 PGA-PCL (65:35) 2.40 1.20 Dioxane 188.0094.00

TABLE V Composition of Casting Solutions Used to Prepare PLA-PGA/PCL-PDOBlends Ingredient Mass (g) Composition (% w/w) Sample Number 1 PLA-PGA(95:5) 11.41 5.70 PCL-PDO (95:5) 0.60 0.30 Dioxane* (g) 188.02 94.00Sample Number 2 PLA-PGA (95:5) 10.81 5.40 PCL-PDO (95:5) 1.21 0.60Dioxane 188.05 94.00 Sample Number 3 PLA-PGA (95:5) 10.21 5.10 PCL-PDO(95:5) 1.80 0.90 Dioxane 188.00 94.00 Sample Number 4 PLA-PGA (95:5)9.59 4.80 PCL-PDO (95:5) 2.40 1.20 Dioxane 188.01 94.00

PLA-PGA films were prepared by pouring the solutions of the filteredsolutions in to a mold after allowing all the bubbles to escape. Thefilms were allowed to dry in nitrogen followed by drying at 45° C. for18 h and at 110° C. for 10 hours.

Mechanical Testing was conducted using the similar method describedearlier.

A summary of the mechanical properties of the PLA-PGA film blends isreported as an average over at least three test specimens in Table VI.

Drugs or bioactive agents, as in earlier described examples, materialsor blends, or other ratios of materials and blends, could be added.

Blends with PGA-PCL

Increasing the PGA-PCL content has a pronounced influence on the stressat yield values. Values decreased from 63 to 20 MPa in going from 5% to20% PGA-PCL in the films. Thus, films become easier to stretch withincreasing PGA-PCL content.

Stress at break values also showed a similar trend, decreasing from ahigh of 55 to 20 MPa with increasing PGA-PCL content in the matrix.

The modulus decreased with increasing PGA-PCL content in the matrix.Values decreased from 3638 to 1413 Mpa in going from 5% to 20% PGA-PCLin the matrix.

TABLE VI Tensile Properties of PLA-PGA Film Blends Cast from DioxaneStress Strain at Stress at Strain at Yield Yield* Modulus* Break atBreak* Sample (MPa) (%) (Mpa) (MPa) (%) Toughness (MPa) Blends ofPLA-PGA (95:5) with PGA-PCL 5% PGA-PCL 62.9 3.68 3638 54.5 7.9 22.4 10%PGA-PCL 55.5 3.75 3247 47.9 11.8 72.0 15% PGA-PCL 28.7 3.39 1669 28.35.0 12.5 20% PGA-PCL 20.4 2.90 1413 20.4 5.2 10.0 Blends of PLA-PGA(95:5) with PCL-PDO 5% PCL-PDO 58.8 3.38 3537 57.4 4.2 14.9 10% PCL-PDO52.7 3.56 3189 45.9 8.6 33.8 15% PCL-PDO 49.8 3.31 2956 49.3 3.3 10.320% PCL-PDO 34.5 3.20 2057 34.4 3.2 5.0 *Strain at yield and strain atbreak as well as the modulus were calculated based on grip separationand not extensometer values.

Blends with PCL-PDO

The same trends were observed for blends of PLA-GA with PCL-PDO;however, the changes in the mechanical properties with increasing PCL-DOwere less pronounced.

Increasing the PCL-PDO content has a marked influence on the stress atyield values. Values decreased from 59 to 35 MPa in going from 5% to 20%PCL-PDO in the films. The change in the modulus is however lesspronounced than with PGA-PCL.

Stress at break values also showed a similar trend, decreasing from ahigh of 57 to 34 MPa with increasing PCL-PDO content in the matrix.

The modulus decreased with increasing PCL-PDO content in the matrix.Values decreased from 3537 to 2057 Mpa in going from 5% to 20% PCL-PDOin the matrix.

(b) Plasticized Polymers Films Prepared from Dioxane:

Blends of poly(lactic acid-co-glycolic acid) (PLA-PGA, 95:5) with threedifferent grades of poly(ethylene glycol) (PEG 600, 1500 and 3442) atlevels of 5%, 10% and 15% of total solids; and

Blends of poly(lactic acid-co-glycolic acid) (PLA-PGA, 95:5) withcitrate ester, Citroflex® A-4 at levels of 5%, 10% and 15% of totalsolids.

Different grades of PEGs and citrate ester were obtained from SigmaAldrich and Morflex, Inc., respectively.

Twelve PLA-PGA casting solutions with various plasticizers at differentlevels were prepared in dioxane. The compositions of these solutions aresummarized in Tables VII and VIII.

The steps used to prepare these casting solutions are summarized below:

Blends of PLA-PGA (95:5) with 5%, 10% and 15% PEG

Weigh and add into amber bottle target mass of PLA-PGA.

Next weigh and add target mass of PEG plasticizer into amber bottlecontaining polymer.

The final PLA-PGA/plasticizer solids content is 6% w/w in dioxane.

Weigh and add target mass of dioxane directly into amber bottlecontaining PLA-PGA and plasticizer. Purge head-space with nitrogen gasand seal the bottle. Tumble overnight (rotational speed=5/min) at 60±2°C.

Blends of PLA-PGA (95:5) with 5%, 10% and 15% Citroflex® A-4

Repeat the procedure described above for preparing blends of PLA-PGA(95:5) with 5%, 10% and 15% Citroflex® A-4.

TABLE VII Composition of Casting Solutions Used to Prepare PLA-PGA Filmswith Citroflex ® A-4 Plasticizer Samples Dioxane (g) 188.04 188.06188.05 PLA-PGA (95:5) (g) 11.42 10.81 10.21 Citroflex ® A-4 (g) 0.621.22 1.83 Total mass (g) 200.08 200.09 200.09 Actual PLA-PGA (% w/w)5.71 5.40 5.10 Actual Citroflex ® A-4 (% w/w) 0.31 0.61 0.92 Mass ofcasting solution 56 g 56 g 56 g poured into rectangular (5 × 7 in²) mold

TABLE VIII Composition of Casting Solutions Used to Prepare PLA-PGAFilms with PEG Plasticizer Samples Dioxane (g) 188.02 188.00 188.04PLA-PGA (95:5) (g) 11.40 10.82 10.20 PEG 600 (g) 0.60 1.20 1.84 Totalmass (g) 200.02 200.02 200.08 Actual PLA-PGA (% w/w) 5.70 5.41 5.10Actual PEG 600 (% w/w) 0.30 0.60 0.92 Mass of casting solution poured 55g 55 g 55 g into rectangular (5 × 7 in²) mold Dioxane (g) 188.01 188.05188.05 PLA-PGA (95:5) (g) 11.42 10.81 10.22 PEG 1500 (g) 0.60 1.22 1.80Total mass (g) 200.03 200.08 200.07 Actual PLA-PGA (% w/w) 5.71 5.405.11 Actual PEG 1500 (% w/w) 0.30 0.61 0.90 Mass of casting solutionpoured 55 g 55 g 55 g into rectangular (5 × 7 in²) mold Dioxane (g)188.03 188.05 188.02 PLA-PGA (95:5) (g) 11.41 10.83 10.24 PEG 3442 (g)0.60 1.21 1.80 Total mass (g) 200.04 200.09 200.06 Actual PLA-PGA (%w/w) 5.70 5.41 5.12 Actual PEG 3442 (% w/w) 0.30 0.61 0.90 Mass ofcasting solution poured 56 g 56 g 56 g into rectangular (5 × 7 in²) mold

PLA-PGA films were prepared by the same method as described earlier forthe polymer blends and the mechanical properties of the films weredetermined.

Mechanical properties of films dried at 110° C. exhibited lower strainvalues due to phase separation between the polymer and the plasticizer.Due to this brittleness, the strain at break values reduced in thepresence of the plasticizers induced by the 110° C. drying conditions.When the films were dried at 60° C., followed by supercritical carbondioxide extraction, the extraction temperature was about 40° C. At 40°C. the films were not brittle. The strain at break values thereforeincreased with increasing amounts of plasticizers.

Helical stents were prepared from PLGA 85/15 with 20% barium sulfate and10% sirolimus (similar to FIG. 6 b). The films that were used to preparethe stents were prepared the same way as described above from dioxane.The main difference was the drying conditions. They were dried at 60° C.for 6 hours followed by supercritical carbon dioxide extraction of theresidual solvent. This drying method provided more than 95% drug contentin the stent. These stents were sterilized by ethylene oxide. Animalstudies were conducted using this stent. It was observed that drugdiffusion at the stented site approximated up to at least 30 mm distaland proximal of the stented site over varying time periods. For example,drug uptake in vessel tissue and drug elution pharmacokinetics isrepresented in the graphs shown in FIGS. 9 and 10.

Helical stents were also prepared from PLGA 85/15 blended with 10%PCL/PGA and contained 30% barium sulfate and 15% sirolimus. The filmswere prepared from dioxane and were also dried at 60° C. for 6 hoursfollowed by supercritical carbon dioxide extraction of the residualsolvent. Animal studies were also conducted using this stent.

Alternatively, the bioabsorbable polymeric materials and additives usedto comprise the drug delivery device according to the systems andmethods of the invention can be solvent cast as tubes as set forth inthe following additional Examples V set forth below. In Examples V thedevices are comprised of bioabsorbable polymeric materials, wherein thebioabsorbable materials are comprised of polylactide/polyglycolidecopolymers such as PLA/PGA (95/5 and 85/15), and/or blends thereof. Asdiscussed above, blends may render polymers more ductile and flexiblewhile maintaining desired stiffness. Different solvents were used toprepare the tubes in the examples. The solvents included chloroform,dioxane, or binary solvent mixtures such as dioxane/acetone anddioxane/ethyl acetate. Different radiopaque materials were also usedincluding barium sulfate, bismuth subcarbonate, bismuth oxide, tungstenand tantalum. The radiopaque materials were used in weights varying from10 to 40% (by weight). Sirolimus was used as the drug in weights varyingfrom 0 to 30% (by weight).

FIG. 8 shows schematically the solvent cast fabrication steps to formtubes. Polymer resins are added to a given solvent and tumbled with orwithout heat until the polymer dissolves completely in the solvent toprovide a homogenous solution. Polymer formulations can be preparedusing these solutions that may include radiopaque agents, drugs orcombinations thereof. These formulations are tumbled and mixed toprepare uniform dispersions. The polymer solution is then deposited ontoa mandrel at room or higher temperature. The deposition may occur at 12mL/hour while the mandrel may revolve at 30 rpm. The mandrel may becoated, for example with Teflon, improve eventual removal therefrom. Asyringe pump, for example, may be used to deposit the polymer solutiononto the mandrel. The mandrel is then dried. The mandrel may be dried ina solvent rich environment and/or a nitrogen rich environment. Thepolymer tube is then removed from the mandrel and may be further driedunder conditions including high temperature oven drying (e.g., 110° C.for 10 hours), low temperature oven drying (e.g., 25° C. to 60° C. for 6hours), low temperature carbon dioxide extraction (e.g., 40° C. at 60 to80 bar pressure for 20 to 60 minutes), lyophilization and combinationsthereof. Low temperature drying is used to preserve drug content in thefilms. The drying conditions will also determine the morphology(amorphous or crystalline) of the tubes. After drying, the tubes canthen be stored in an inert environment (nitrogen box) until furthertesting and prototyping.

EXAMPLE V

Preparation of Polymer Tubes (PLA/PGA 95/5) with Sirolimus fromChloroform:

The objective of the work was to develop methods for fabricating tubingout of a solution of biodegradable PLA/PGA copolymers in a solvent withvarying sirolimus drug content. Tubes were prepared with drug loadingsof 0, 5, 10, 15, 20 and 30 wt % sirolimus. The solution was delivered toa Teflon coated mandrel at a set flow rate for a given drugconcentration to give a continuous layer of solution of constantthickness, wherein the solution delivery rate decreases as theconcentration of drug increases. The final thickness of the tube wallwas determined by the solution concentration and the laydown rate of thesolution onto the mandrel, which in turn is determined by the pumpingrate and the mandrel speed. A solvent chamber is used to reduce theevaporation rate of the solvent from the coated mandrel so as to avoidbubble formation in the coating as it dries.

Exemplary specifications for the tubes were:

Tube Parameter Target Inside diameter 1 and 3.50 mm Length 25 mm Wallthickness 0.005 to 0.010 inches (127 to 2504 μm)

The materials used were:

Component Amount Percent 95/5 PLA/PGA  14.53 grams 8.30% Chloroform,Sigma-Aldrich, HPLC grade, 160.47 grams 91.70% water content less than0.01%

Drugs or bioactive agents may also be added as in earlier describedexamples.

The following processing conditions were used for Example V:

Prepare and provide an 8.3 wt % solution of the PLA/PGA & adddrugs/agents as desired. (Sirolimus is added in appropriate amounts tothis solution to prepare differing PLA/PGA polymer to drug ratios).

Set the apparatus conditions as follows:

-   -   Mandrel RPM=34.5    -   Position stage speed=4.11 cm/min

Set the solution dispense rate according to the amount of total solidsin the solution formulation. (With no drug in the formulation thedispense rate is 38 mL/hour, whereas with 30% sirolimus the rate is 28mL/hour. The rates are ideally calculated so as to give a consistentthickness (0.15 mm) of the dried tube.)

Provide chloroform solvent in the bottom of the solvent chamber to adepth of approximately 1 cm, place the mandrel into the solvent chamber,and then place the mandrel/solvent chamber into the apparatus.

Dispense the solution onto the mandrel using the conditions specifiedabove. Full deposition is ideally achieved in one pass.

Rotate the coated mandrel in the solvent chamber for at least 45additional minutes. (During this period, relatively little air flowsover the solvent chamber so as to minimize the drying rate.)

Remove the coated mandrel from the solvent chamber and placed themandrel in the nitrogen purge chamber for room temperature drying for atleast 1.5 hours. The purge rate is fairly low (0.5 to 1 SCFH).

After initial drying, place mandrel into oven at 40°-60° C. for about 10minutes.

Remove the mandrel from the oven and clamp one free end.

Break the adhesion of the tube on the mandrel by gently twistingsections of the tube.

Remove the tube from the mandrel by pushing the tube off of the mandrel.

Trim the ends of the tube and replace the tube onto the mandrel.

Place the mandrel and tube into the oven for further drying to removeresidual solvents.

Remove the mandrel and tube from the oven and slip the tube off of themandrel.

Store tubes in sealed vials until needed.

PLA/PGA (95:5) tubes having fairly constant wall thicknesses whilecontaining various amounts of the drug sirolimus were produced as aresult of the above process, as set forth in Table X below:

TABLE X Summary of PLA/PGA (95:5) Tubes Sirolimus Content Wall Thicknessnone ~0.15 to 0.18 mm (0.006″ to 0.007″)  5% ~0.15 to 0.16 mm (0.006″)10% ~0.15 to 0.17 mm (0.006″ to 0.007″) 15% ~0.18 mm (0.007″) 20% ~0.15to 0.18 mm (0.006″ to 0.007″) 30% ~0.15 mm (0.006″)

EXAMPLE VI

Tubes Prepared from PLA/PGA (85/15) with Sirolimus from Chloroform:

These PLA/PGA (85:15) tubes were prepared using similar steps asidentified in Example V except with a mandrel condition of 31 RPM and astage speed of 4.1 cm/min. As before, the solution delivery ratedecreases as the sirolimus drug concentration increases so as tomaintain a fairly uniform wall thickness in the tubes produced thereby.

The specifications for the tubes were:

Tube Parameter Target Inside diameter 1 and 3.50 mm Length 25 mm Wallthickness 0.005 to 0.006 inches (0.127 to 0.152 mm)

The materials used were:

Material 85/15 PLA/PGA copolymer Chloroform, Sigma-Aldrich 99.9+ HPLCgrade, 0.5% ethanol stabilizer, water content less than 0.01% Sirolimus,refrigerated at 4° C.

PLA/PGA (85:15) tubes having fairly constant wall thicknesses whilecontaining various amounts of the drug sirolimus dispensed at variousrates were produced as a result of the above process, as set forth inTable XI below:

TABLE XI Summary of 85/15 PLA/PGA Tubes Sirolimus Wall Thickness None0.14 to 0.15 mm  5% 0.15 mm 10% 0.14 to 0.15 mm 15% 0.15 mm 20% 0.14 to0.15 mm 30% 0.15 mm

EXAMPLE VII

Tubes Prepared from PLA/PGA 95/5 with Radiopaque Agents from Chloroform:

Tubes were formed with PLA/PGA 95/5 copolymer and 10, 20, and 30 wt %BaSO₄ and (BiO)₂CO₃ as x-ray opacifiers for the tubes. The tube sizingspecifications were the same as in Examples V & VI.

The following materials were used in the preparation of the tubes:

Material 95:5 PLA/PGA copolymer Chloroform, Sigma-Aldrich, 99.9+ HPLCgrade, 0.5% ethanol stabilizer, water content less than 0.01% Bariumsulfate, BaSO₄ Bismuth subcarbonate, (BiO)₂CO₃

The PLA/PGA material was received dry and stored under high vacuum priorto use. The chloroform was used as received.

The bismuth subcarbonate and barium sulfate were dried at 110° C. for 24hours then stored under nitrogen prior to use.

Preparation

The apparatus and procedure for preparing the tubes was the same asdescribed earlier with respect to Example V, wherein 10 wt % PLA/PGA(95:5) was used.

As the concentration of the radiopaque material increased the solutiondelivery rate decreased in order to maintain a uniform wall thickness ofthe tube. Because the density of the radiopaque materials is generallynot as great as the density of the drug sirolimus, for instance, thedelivery rate is generally not decreased as much as might occur tocompensate for an increased drug concentration in the solution. Based onthe preceding method the following radiopaque coating solutions wereprepared:

These 10 wt % PLA/PGA (95:5) solutions with BaSO₄ or (BiO)₂CO₃ addedthereto were then used to prepare tubes under the following conditions:

Dispenser Solution Mandrel Nozzle Speed Delivery Rate RPM (cm/min)(mL/hour) 31 4.1 38 31 4.1 36 31 4.1 34 31 4.1 37 31 4.1 35.5 31 4.135.5

The stent tubes were dried as above.

Radiopaque Tube Samples Prepared

A list of the sample tubes prepared is shown in Tables XII and XIII,wherein the tubes were thereafter packed in vials and sealed untildesired.

TABLE XII BaSO₄ Sample Tubes BaSO₄ Amount in Solids Wall Thickness 10%0.16 to 0.17 mm 20% 0.15 to 0.17 mm 30% 0.15 mm

TABLE XIII (BiO)₂CO₃ Sample Tubes (BiO)₂CO₃ in Sample Wall SolidsThickness 10% 0.14 to 0.15 mm 20% 0.15 mm 30% 0.15 mm

Similar tubes were prepared from PLA/PGA 85/15 with 30% barium sulfate;and with 30% barium sulfate and PCL/PGA blend from dioxane.

The various bioabsorble polymers, blends, drugs, bioactive agents andsolvent described herein may be used to fabricate tubes according thesystems and methods as described herein.

The bioabsorbable materials used to form the drug delivery device arechosen as discussed herein in order to achieve the desired flexibility,mechanical integrity, degradation rates, shape, geometry and pattern ofthe device. Plasticizers can be added to the matrix of bioabsorbablepolymer materials, if desired, in order to render the device even moreflexible. The plasticizers are added to the bioabsorbable materials ofthe device prior to or during processing thereof. The plasticizers arepreferably materials of lower molecular weight than the bioabsorbablematerials that are being processed to comprise the device. Adding theplasticizers renders the bioabsorbable materials more flexible andtypically reduces processing temperatures. As a result, degradation ofdrugs incorporated into the bioabsorbable materials having plasticizersadded thereto during processing is further minimized. Melt extrusiontemperatures can also be lowered by adding different solvents to thepolymer before or during extrusion. Blends of polymers, with meltingpoints lower than the melting point of the bioabsorbable materials inwhich the drugs or other bio-active agents are to be incorporated, mayalso be added to the bioabsorbable materials that are to comprise thedevice. Adding the blends of polymers having the lower melting pointsalso helps to reduce processing temperatures and minimize degradation ofthe drugs or agents thereby.

In the case of a stent device comprised of bioabsorbable materialsformed by co-extrusion, different bioabsorbable polymeric materials maybe used whereby the different polymer tubes are extruded generally atthe same time to form a sheath and a core, respectively, of the stent.Bioabsorbable polymeric materials having low melting points are extrudedto form the sheath or outside surface of the stent. These low meltingpoint materials will incorporate the drugs or other bio-active agentsfor eventual delivery to the patient, whereas materials having highermelting points are extruded to form the core or inside surface of thestent that is surrounded by the sheath. The higher melting pointmaterials comprising the core will thus provide strength to the stent.During processing, the temperatures for extruding the low melting pointdrug containing materials (e.g., polycaprolactone and/or polydioxanone)can be as low as 60° C. to 100° C. Further, because the drugs or otherbio-active agents added to the devices made by this co-extrusion methodtend to be coated onto the device after the device has been extruded,the drugs or agents are not exposed to the high temperatures associatedwith such methods. Degradation of the drugs during processing isminimized therefore. Because the co-extrusion of different tubesrequires fairly precise co-ordination, stents of simpler shapes tend tobe formed using this co-extrusion method. Radiopaque agents may beincorporated into the device during or after extrusion thereof.

In the case of a stent device comprised of bioabsorbable polymericmaterials formed by co-mingled fibers, different bioabsorbable polymericmaterials may also be used. Contrary to the co-extrusion techniquesdescribed above, the co-mingled fibers technique requires that eachfiber be separately extruded and then later combined to form a stent ofa desired geometry. The different bioabsorbable polymeric materialsinclude a first fiber having a low temperature melting point into whicha drug is incorporated, and a second fiber having a higher temperaturemelting point. As before, radiopaque agents may be added to one or moreof the fibers during, or after, extrusion thereof.

In the case of a stent comprised of bioabsorbable materials formed bysupercritical fluids, such as supercritical carbon dioxide, thesupercritical fluids are used to lower processing temperatures duringextrusion, molding or otherwise conventional processing techniques.Different structures, such as fibers, films, or foams, may be formedusing the supercritical fluids, whereby the lower temperature processingthat accompanies the supercritical fluids tends to minimize degradationof the drugs incorporated into the structures formed.

Drug delivery devices or stents, as described herein, may also be madewith or without drugs, agents or radiopaque materials added thereto asfrom compression molded films, for example. In the case of devices madefrom compression molded films, PLLA, PLGA (85/15), PLGA (95/5) or otherbioabsorbable materials may be used. Once prepared the films are cutinto film strips of lengths as desired and converted to a geometry asdesired. Where the film strips are to be converted into helical coilstents such as shown in FIGS. 1-3, the strips, once cut, are placed ontoa heated mandrel and heated to above the glass transition temperature ofthe polymer. Lower profile stents may be achieved by using a mandrelwith a smaller outer diameter. The helical coiled strips are thentransferred to a balloon catheter and nested at different pressures(200-220 psi) and temperatures (60-100° C.) using nesting tubes (e.g.,0.0067 mils) in order to achieve stepwise reductions in the stentdiameter. Thereafter, the nested stents are deployed in a water bath at37° C. at nominal pressures (8-12 psi) in silicon tubings.

Radial strength of such stents formed from compression molded filmsvaries depending on the geometry or design of the device and the wallthickness.

While the above described systems and methods of the invention havefocused primarily on stent devices comprised of bioabsorbable polymericmaterials with drugs and radiopaque materials added thereto, the artisanwill appreciate that devices other than stents may as well be comprisedof bioabsorbable materials with drugs and radiopaque materials accordingto the systems and methods of the invention. As with stents, the devicesmay take on different geometries according to the techniques used toform the devices, whereby melt compounded blends of bioabsorbablematerials, drugs and radiopaque materials may be melt spun into fibers,compression molded into discs or rings, extruded into tubes or injectionmolded into more intricate devices. Solution processing may instead beused to form the non-stent devices whereby super critical fluids, suchas carbon dioxide, or other solvent extraction, extrusion or injectionmolding techniques may also be used to minimize degradation of the drugsor other agents by reducing the processing temperature to which thebioabsorbable materials are subjected.

As with the earlier described stent drug delivery devices, differentgeometries of non-stent drug delivery devices formed by the variousprocesses can also be achieved. After processing, the fibers, tube,films, discs, rings, or other geometry of the non-stent devices may belaser cut and/or braided into a desired shape or pattern.

While there has been shown and described what is considered to bepreferred embodiments of the invention, it will, of course, beunderstood that various modifications and changes in form or detailcould readily be made without departing from the spirit or scope of theinvention. It is therefore intended that the invention be not limited tothe exact forms described and illustrated herein, but should beconstrued to cover all modifications that may fall within the scope ofthe appended claims.

1. An implantable drug delivery device comprising: at least onebioabsorbable polymer and at least one drug or bio-active agentincorporated into a solvent cast film formed at low temperatures; astrip cut from the film, the strip having a pair of opposed sides and apair of opposed ends; and a tubular structure formed from the strip bymanipulation thereof.
 2. The implantable drug delivery device of claim1, further comprising a radiopaque material incorporated into, or onto,the device.
 3. The implantable drug delivery device of claim 1, whereinthe tubular structure further comprises a helical structure comprising astent having a solid ladder configuration between ends thereof.
 4. Theimplantable drug delivery device of claim 3, wherein each of the opposedends are angled 10-30°, and preferably 20°, relative to a respective oneof the opposed sides of the stent.
 5. The implantable drug deliverydevice of claim 1, wherein the tubular structure further comprises ahelical structure comprising a stent having an open lattice structurebetween ends thereof.
 6. The implantable drug delivery device of claim4, wherein each of the opposed ends are angled 10-30°, and preferably20°, relative to a respective one of the opposed sides of the stent. 7.The implantable drug delivery device of claim 6, wherein the openlattice structure comprises struts laser cut into the film.
 8. Theimplantable drug delivery device of claim 1, wherein the tubularstructure further comprises a helical structure comprising a stenthaving a hybrid structure including solid ladder and open latticeportions between ends thereof.
 9. The implantable drug delivery deviceof claim 8, wherein each of the opposed ends are angled 10-30°, andpreferably 20°, relative to a respective one of the opposed sides of thestent.
 10. The implantable drug delivery device of claim 1, wherein theat least one bioabsorbable polymer further comprises at least one of abulk erosion polymer and a surface erosion polymer.
 11. The implantabledrug delivery device of claim 10, wherein the tubular structure furthercomprises a ring or wrap.
 12. The implantable drug delivery device ofclaim 1, wherein the incorporation of the at least one drug orbio-active agent into the solvent cast film formed at low temperatureprovides improved drug diffusion and tissue uptake.
 13. The implantabledrug delivery device of claim 12, wherein the drug diffusion and tissueuptake varies over time based on the at least one bioabsorbable polymerand the at least one drug or bio-active agent incorporated into thefilm.
 14. A method of forming a drug delivery device, the methodcomprising: co-extruding different bioabsorbable polymer tubes at onetime to form a sheath and a core of a stent, wherein the materialshaving lower melting points comprise the sheath and incorporate at leastone drug or other bioactive agent, and the materials having highermelting points comprise the core of the stent.
 15. The method of claim14, wherein the materials comprising the sheath comprises at least oneof polycaprolactone and polydioxanone.
 16. The method of claim 14,further comprising coating the drugs or bioactive agents onto the deviceafter extrusion thereof.
 17. The method of claim 14, further comprisingincorporating radiopaque materials into, or onto, the device.
 18. Amethod of forming a drug delivery device comprising: co-minglingdifferent bioabsorbable polymeric fibers that are separately extrudedand later combined to form the device.
 19. The method of claim 18,further comprising at least a first bioabsorbable polymeric fiber and asecond bioabsorbable polymeric fiber, the first fiber having a lowermelting point than the second fiber, wherein at least one drug or otherbioactive agent is incorporated into the first fiber.
 20. The method ofclaim 19, further comprising incorporating radiopaque material into, oronto, the device.